This invention relates to novel compositions comprising one or more of an acid protease enzyme and an acidic buffer, the acidic buffer comprising an acidic buffering component that can reversibly disassociate hydrogen ions and has buffering capacity at pH values below that of the surface of the skin, i.e., approximately pH 5.5. and a pharmaceutically or cosmetically acceptable carrier, useful for treating or preventing abnormal skin conditions, diseases or disorders, and/or for improving the texture or appearance of the skin, and/or for enhancing epidermal exfoliation, and/or for enhancing epidermal cell renewal and to methods for the use of the compositions.
It is well founded that exfoliation of epidermal layers of human skin induces an increased rate of epidermal cell renewal (E. Phillips, 1995, U.S. Pat. No. 5,431,913; W. P. Smith, 1994, Cosmetics and Toiletries 109:41-8). The human epidermis consists of multiple layers of stratified squamous epithelial cells in a constant state of renewal. New cells are formed first in the basal layer, which is the most internal membrane of the epidermis. These cells are displaced by the production of yet newer cells and subsequently are transported to the external layer of the epidermis, the stratum corneum, where they usually are shed (exfoliated) every two to three weeks. The general health and appearance of human skin depends greatly upon the rate of this process.
Reference is made to U.S. Pat. No. 5,976,556. Application Ser. No. 09/354,687, filed Jul. 16, 1999, referenced above, is a divisional application of U.S. Pat. No. 5,976,556.
The present invention provides novel pharmaceutical and/or cosmetic compositions for treating or preventing abnormal skin conditions, diseases or disorders, and/or for improving the texture or appearance of the skin, and/or for enhancing epidermal exfoliation, and/or for enhancing epidermal cell renewal. The compositions comprise one or more of an acid protease and an acidic buffer. For purposes of this invention, the acid protease is an enzyme which exhibits peptidyl hydrolase (proteolytic) activity below the average pH of the surface of the skin and is significantly inactive at a pH greater than the average pH of the surface of the skin, which is about pH 5.5 for humans (W. P. Smith, 1994, Cosmetics and Toiletries 109:41-8). For men the average pH of the surface of the skin is about pH 5.3 and for women it is about pH 6.0 (Ohman and Vahlquist, 1994, Acta Dermato-Venereol. 74(5):375-379). For purposes of this invention, the average pH of the surface of the skin which is about pH 5.5 includes, in addition to others, gender-specific variations, such that a pH of about 5.5 includes a range of about pH 5.3, the average pH of the surface of a man""s skin, up to about pH 6.0, the average pH of the surface of a woman""s skin. Preferably, at a pH greater than or equal to the average pH of the surface of the skin (approximately pH 5.3-6.0), the acid proteases useful in this invention exhibit less than about 10% of the enzymatic activity they exhibit at their respective optimal pHs below the average pH of the surface of the skin.
The acid protease can be in the apoenzyme, holoenzyme, isoenzyme, or zymogen form. The acid protease component of the composition can be present in an amount of about 0.001% to about 99.999% by weight of the final composition, preferably about 0.1% to about 50%, more preferably about 1% to about 5%. The protease(s) has a specific activity of about 1.0 to about 10,000 HUT units/mg as determined by the method, as modified, described in Food Chemicals CODEX, 3rd ed., (1981), pp. 496-497, National Academy Press, Washington, D.C., see infra, Section 5.1. Preferably the protease(s) has a specific activity of about 50 to about 3000 HUT units/mg, more preferably about 500 to about 1500 HUT units/mg.
The acidic buffer is a composition which when topically applied to the skin, temporarily lowers the pH of the surface of the skin to less than about pH 5.5 but not lower than about pH 1.0, preferably to between about pH 2.5 and about pH 4.5. The acidic buffer composition comprises at least one of an acidic buffering component that can reversibly disassociate hydrogen ions and has buffering capacity at a pH values below that of the surface of the skin, i.e., approximately pH 5.5 and a pharmaceutically or cosmetically acceptable carrier, vehicle or excipient. The acidic buffering component of the acidic buffer can be an organic acid, an inorganic acid or mixtures thereof. The acidic buffer is susceptible to neutralization to the average pH of the surface of the skin over time by natural epidermal processes, such as perspiration. The time period required for neutralization, and subsequent inactivation of the protease, will depend on the formulation of the acidic buffer. For example, shorter time periods result if the acidic buffer contains a weak acid or a weak buffering agent to counteract the relative alkalinity of the epidermis; longer time periods result if a stronger acid is utilized or a stronger buffering agent is employed in the acidic buffer. The acidic buffering component of the acidic buffer of the composition can be an organic acid or inorganic acid that can reversibly disassociate hydrogen ions and has buffering capacity at pH values below that of the surface of the skin, i.e., approximately pH 5.5 or mixtures thereof and can be present in an amount of about 0.001% to about 99.999% by weight of the final composition, preferably about 0.01% to about 25%, more preferably about 1.0% to about 5%.
Control of the time period required for the pH of the surface of the skin to return to a pH of about 5.5 after topical application of a composition of the present invention allows for control of the activity of the protease enzyme. It is through this control of proteolytic activity that the present invention overcomes the drawbacks and complications found in the prior art, such as itching, burning, blistering, etc., caused by broad pH spectrum proteolytic enzymes. The period of time it takes for the surface pH of the skin to return to about pH 5.5 is determined by a number of factors, including the type of skin condition, disease or disorder that is being treated and the sensitivity of the skin of the particular subject being treated. To avoid the drawbacks and complications found in the prior art, ideally, the period of time should not exceed about 4 hours for any individual application of a composition of the present invention, preferably the period of time is between about 5 minutes to about 4 hours, more preferably between about 30 minutes to about 2 hours, most preferably between about 30 minutes to about one hour.
It is to be pointed out that the pharmaceutical compositions of the present invention are those which, when administered to the skin, render a benefit or an effect of treating or preventing an abnormal biological condition, disease, or disorder. Benefits or effects of treating or preventing such abnormal condition, disease, or disorder are the reduction in severity or disappearance of the symptoms or cause of the abnormal condition, disease, or disorder. The reduction in severity or disappearance of the abnormal condition, disease, or disorder may be either in the short- or long-term. Such abnormal biological conditions, diseases, or disorders to be treated by administering a composition of the present invention include, but are not limited to, dry skin, severe dry skin, dandruff, acne, keratoses, eczema, skin flakiness, pruritus, age spots, lentigines, melasmas, wrinkles (both coarse and fine, caused by intrinsic as well as extrinsic damage), warts, blemished skin, hyperpigmented skin, hyperkeratotic skin, inflammatory dermatoses, age-related skin changes and skin in need of cleansers, as well as the effects of skin atrophy and psoriasis.
It is to be further pointed out that the cosmetic compositions of the present invention are those which, when administered to the skin, improve the texture or appearance thereof or enhance epidermal exfoliation and/or epidermal cell renewal, without necessarily rendering a benefit or an effect of treating or preventing an abnormal biological condition, disease, or disorder. In this context, improving the texture or appearance of the skin or enhancing epidermal exfoliation and/or epidermal cell renewal is meant to encompass providing a natural-looking and/or natural-feeling coating over the skin so as to enhance the beauty and/or smoothness of the skin from its pre-treated state, or to mask unwanted symptoms of an abnormal biological condition, disease, or disorder. This can include providing a temporary moisturizing effect to the epidermis. Such abnormal biological conditions, or diseases include, but are not limited to dry skin, severe dry skin, dandruff, acne, keratoses, psoriasis, eczema, skin flakiness, pruritus, age spots, lentigines, melasmas, wrinkles (both coarse and fine, caused by intrinsic as well as extrinsic damage), warts, blemished skin, hyperpigmented skin, hyperkeratotic skin, inflammatory dermatoses, age-related skin changes and skin in need of cleansers, as well as the effects of skin atrophy, and psoriasis.
In yet another embodiment, the invention encompasses methods for treating abnormal skin conditions, diseases, or disorders including but not limited to dry skin, severe dry skin, dandruff, acne, keratoses, psoriasis, eczema, skin flakiness, pruritus, age spots, lentigines, melasmas, wrinkles (both coarse and fine, caused by intrinsic as well as extrinsic damage), warts, blemished skin, hyperpigmented skin, hyperkeratotic skin, inflammatory dermatoses, age-related skin changes and skin in need of cleansers. The method comprises topically administering to an area of a subject""s skin having the condition, disease, or disorder an effective amount of a composition comprising an acid protease which is enzymatically active below about pH 5.5 and an acidic buffer which lowers the surface pH of the skin to below about pH 5.5 for a period of time effective for the treatment of the condition, disease, or disorder, the acidic buffer being subject to neutralization by normal epidermal processes.
In yet another embodiment, the present invention provides methods for the enhancement of epidermal exfoliation and/or epidermal cell renewal comprising topically administering to an area of a subject""s skin an effective amount of a composition comprising an acid protease which is enzymatically active below about pH 5.5 and an acidic buffer which lowers the surface pH of the skin to below about pH 5.5 for a period of time effective for enhancing epidermal exfoliation and/or epidermal cell renewal, the acidic buffer being subject to neutralization by normal epidermal processes.
In another embodiment, the invention provides methods for improving the texture or appearance of the skin comprising topically administering to an area of a subject""s skin an effective amount of a composition comprising an acid protease which is enzymatically active below about pH 5.5 and an acidic buffer which lowers the surface pH of the skin to below about pH 5.5 for a period of time effective to improve the texture or appearance of the skin, the acidic buffer being subject to neutralization by normal epidermal processes.
In a still further embodiment, the invention provides methods for regulating the effects of skin atrophy comprising administering to an area of a subject""s skin an effective amount of a composition comprising an acid protease which is enzymatically active below about pH 5.5 and an acidic buffer which lowers the surface pH of the skin to below about pH 5.5 for a period of time effective for regulating the effects of skin atrophy, the acidic buffer being subject to neutralization by normal epidermal processes.
The compositions and methods of the present invention surprisingly demonstrate pharmaceutical activity or cosmetic effects against skin disorders heretofore not achieved by acids, .alpha.-hydroxycarboxylic acids, salicylic acids or broad pH spectrum proteases by themselves.
Definitions
As used in the present invention the following terms are intended to encompass the following:
ACIDIC BUFFER: A composition comprising an acidic buffering component and a pharmaceutically or cosmetically acceptable carrier, vehicle or excipient which when topically applied to the skin lowers the surface pH of the skin to below about pH 5.5 and is subject to neutralization by natural skin processes such that the natural skin processes, over time, return the pH of the skin""s surface to normal, which is about pH 5.5. The acidic buffering component of the acidic buffer can be an organic acid, an inorganic acid, or mixtures thereof that can reversibly disassociate hydrogen ions and has buffering capacity at pH values below that of the surface of the skin, i.e., approximately pH 5.5 and a pharmaceutically or cosmetically acceptable carrier, vehicle or excipient. The acidic component of the acidic buffer can be a monomer, polymer, or mixtures thereof. The acidic component of the acidic buffer can be the acid protease itself.
ACID PROTEASE: An enzyme which exhibits peptidyl hydrolase (proteolytic) activity at a pH below the average normal pH of the skin""s surface, which is about pH 5.5, and which is significantly inactive at a pH greater than or equal to such average normal skin surface pH, i.e., less than about 10% activity at about pH 5.5 or greater as compared to peak activity at pH less than about pH 5.5. The acid protease can be in the apoenzyme, holoenzyme, isoenzyme or zymogen form.
COSMETIC: A formulation to be administered to the skin which improves the texture or appearance thereof, without necessarily rendering a benefit or an effect of treating or preventing an abnormal biological condition or a disease. Such improvement includes providing a temporary moisturizing effect to the mammalian epidermis.
EFFECTIVE AMOUNT: An amount of composition sufficient to significantly induce a positive modification in the condition to be treated, but low enough to avoid serious side effects. The effective amount of the composition will vary with the particular condition being treated, the age and physical condition of the subject being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the specific composition employed, the particular pharmaceutically-acceptable carrier or cosmetically-acceptable carrier utilized, and similar factors within the knowledge and expertise of those skilled in the art.
EPIDERMAL CELL RENEWAL: The process by which new skin cells are formed in the basal layer, are transported to the external layer, the stratum corneum, and subsequently are exfoliated and replaced by yet newer skin cells.
EXFOLIATION: The detachment and shedding of superficial cells of an epithelium or from any tissue surface.
PHARMACEUTICAL: A formulation to be administered to the skin which renders a benefit or an effect of treating or preventing an abnormal biological condition or a disease.
REGULATING SKIN ATROPHY: The preventing, retarding, arresting, treating, or reversing the process of atrophy in mammalian skin.
SKIN ATROPHY: The thinning and/or general degradation of the dermis layer of mammalian skin often characterized by a decrease in collagen and/or elastin as well as decreased number, size and doubling potential of fibroblast cells. Skin atrophy is a natural result of aging, but may be caused by either intrinsic or extrinsic factors such as natural chronoaging, photodamage, burns or chemical damage, or by exposure to pollutants or allergens, e.g., cigarette smoke. Skin atrophy is often an undesirable side effect resulting from treatment with xcex1-hydroxycarboxylic acids or salicylic acids.
The present invention may be understood more fully by reference to the detailed description and illustrative examples which are intended to exemplify non-limiting embodiments of the invention.